Synthesis of Monosaccharide‐Derived Spirocyclic Cyclopropylamines and Their Evaluation as Glycosidase Inhibitors

The glucose‐, mannose‐, and galactose‐derived spirocyclic cyclopropylammonium chlorides 1a – 1d, 2a – 2d and 3a – 3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl acrylate led in 71% yield to a 4 : 5 : 1 : 20 mixture of the ethyl cyclopropanecarboxylates 7a – 7d , while the Cu‐catalysed cycloaddition of ethyl diazoacetate to the exo ‐glycal 6 afforded 7a – 7d (6 : 2 : 5 : 3) in 93–98% yield ( Scheme 1 ). Saponification, Curtius degradation, and subsequent addition of BnOH or t‐ BuOH led in 60–80% overall yield to the Z‐ or Boc‐carbamates 11a – 11d and 12a – 12d , respectively. Hydrogenolysis of 11a – 11d afforded 1a – 1d , while 12a – 12d was debenzylated to 13a – 13d prior to acidic cleavage of the N ‐Boc group. The manno ‐ and galacto ‐isomers 2a – 2d and 3a – 3d , respectively, were similarly obtained in comparable yields ( Schemes 2 and 4 ). Also prepared were the differentially protected manno‐ configured esters 24a – 24d ; they are intermediates for the synthesis of analogous N ‐acetylglucosamine‐derived cyclopropanes ( Scheme 3 ). The cyclopropylammonium chlorides 1a – 1d, 2a – 2d and 3a – 3d are very weak inhibitors of several glycosidases ( Tables 1 and 2 ). Traces of Pd compounds, however, generated upon catalytic debenzylation, proved to be strong inhibitors. PdCl $\rm{_{4}^{2-}}$ is, indeed, a reversible, micromolar inhibitor for the β‐ glucosidases from C. saccharolyticum and sweet almonds (non‐competitive), the β ‐galactosidases from bovine liver and from E. coli (both non‐competitive), the α ‐galactosidase from Aspergillus niger (competitive), and an irreversible inhibitor of the α ‐glucosidase from yeast and the α ‐galactosidase from coffee beans. The cyclopropylamines derived from 1a – 1d or 3a – 3d significantly enhance the inhibition of the β‐ glucosidase from C. saccharolyticum by PdCl $\rm{_{4}^{2-}}$ , lowering the K i value from 40 μ M (PdCl $\rm{_{4}^{2-}}$ ) to 0.5 μ M for a 1 : 1 mixture of PdCl $\rm{_{4}^{2-}}$ and 1d . A similar effect is shown by cyclopropylamine, but not by several other amines.